Sitagliptin phosphate is a selective inhibitor of the second generation dipeptidyl peptidase IV (DPP-4) and used to maintain the systemic concentration of incretin hormone at an optimum level. Sitagliptin phosphate monohydrate was approved in October 2006 by the US Food and Drug Administration (FDA) as an adjuvant in dietetics or kinesiatrics for treatment of patients with type-2 diabetes and it is marketed in the United States and Korea under the trade name of JANUVIA™ (as a single agent).
Various methods for preparing sitagliptin and sitagliptin phosphate have been developed. For example, International Patent Publication WO 2003/004498 discloses a method of introducing a chiral-amine group using a chiral pyrazine derivative and to prepare sitagliptin by Arndt-Eistert Homologation using t-butoxylcarbonylamino-4-(2,4,5-trifluorophenyl)-butyric acid as a sitagliptin intermediate, as shown in Reaction Scheme 1.
Wherein,Boc is tert-butoxycarbonyl, TEA is trimethylamine, HOBt is 1-hydroxybenzotriazole, EDC is N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide, and DIPEA is N,N-diisopropylethylamine.
International Patent Publication WO 2004/087650 discloses a method for preparing sitagliptin phosphate comprising the steps of: subjecting (2,4,5-trifluorophenyl)acetic acid to two-step reactions to obtain methyl 4-(2,4,5-trifluorophenyl)-3-oxophenylbutylate; conducting a stereoselective reduction of the resulting compound in the presence of (S)-BINAP-RuCl2.Et3N under a high hydrogen pressure; hydrolyzing the reduced product to obtain (3S)-3-hydroxy-4-(2,4,5-trifluorophenyl)-butyric acid, a key sitagliptin intermediate; and subjecting (3S)-3-hydroxy-4-(2,4,5-trifluorophenyl)-butyric acid to seven-step processes to obtain sitagliptin phosphate, as shown in Reaction Scheme 2.
Wherein,BINAP is 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, EDC is N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide, Bn is benzyl, DIAD is diisopropyl azodicarboxylate, NMM is N-methylmorpholine, and ACN is acetonitrile.
Further, International Patent Publication WO 2004/085661 discloses a method for preparing sitagliptin by stereoselectively reducing an enamine using a platinum catalyst, PtO2, as shown in Reaction Scheme 3.

Further, WO 2005/097733 discloses a method for preparing sitagliptin by stereoselectively reducing an enamine employing a rhodium-based catalyst, [Rh(cod)Cl]2 having a chiral diphosphine ligand, as shown in Reaction Scheme 4.

The document [J. Am. Chem. Soc., 2009, 131, p. 11316-11317] discloses a method for preparing sitagliptin by stereoselectively reducing an enamine using a ruthenium-based catalyst, Ru(OAc)2 having a chiral diphosphine ligand, and International Patent Publication WO 2009/064476 discloses a method for preparing sitagliptin by stereoselectively reducing an enamine using Ru(OAc)2 and a chiral diphosphine ligand, or using a chiral acid together with a borohydride reducing agent (e.g., NaBH4).
The present inventors have endeavored to develop an improved method for preparing sitagliptin using a novel intermediate, and unexpectedly found that sitagliptin can be prepared by a simple and low-cost method using a chiral oxirane prepared from the commercially available epichlorohydrin.